Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 6, Pages 2152-2156Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1201753109
Keywords
TRP63; rare disease; cornea
Categories
Funding
- European Union [LSHB-CT-2005-019067]
- Agence Nationale de Recherche [ANR-08-GENOPAT-024-03, ANR-erare2-SkinDev]
- Israel Ministry of Science and Technology [MOST3-6494]
- Institut National de la Sante et de la Recherche Medicale
- Embassy of France in Israel
- European Molecular Biology Organization short-term fellowship
- Israeli ministry of integration
- Else-Kroner Fresenius Stiftung fellowship
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Ectodermal dysplasia is a group of congenital syndromes affecting a variety of ectodermal derivatives. Among them, ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome is caused by single point mutations in the p63 gene, which controls epidermal development and homeostasis. Phenotypic defects of the EEC syndrome include skin defects and limbal stem-cell deficiency. In this study, we designed a unique cellular model that recapitulated major embryonic defects related to EEC. Fibroblasts from healthy donors and EEC patients carrying two different point mutations in the DNA binding domain of p63 were reprogrammed into induced pluripotent stem cell (iPSC) lines. EEC-iPSC from both patients showed early ectodermal commitment into K18(+) cells but failed to further differentiate into K14(+) cells (epidermis/limbus) or K3/K12(+) cells (corneal epithelium). APR-246 (PRIMA-1(MET)), a small compound that restores functionality of mutant p53 in human tumor cells, could revert corneal epithelial lineage commitment and reinstate a normal p63-related signaling pathway. This study illustrates the relevance of iPSC for p63 related disorders and paves the way for future therapy of EEC.
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